May 3, 2012

New Data Improve Understanding Of Breast Cancer’s Multiple Varieties

New findings presented at Europe's leading breast cancer translational research conference this year shed new light on the many biological differences between individual breast cancers.

Focused on the biological features that make tumors more or less sensitive to important therapies, the new studies will help doctors make crucial choices about the most appropriate treatment for millions of patients.

"Despite major advances in the treatment of breast cancer many patients continue to relapse and die from the disease," noted Prof Mitch Dowsett from the Royal Marsden Hospital, UK, former IMPAKT Chair. "Studies presented at this year's IMPAKT further emphasize the potential of biomarkers to identify new targets for developing therapy to disease that is resistant to our current treatments as well as the groups of patients most likely to respond to the new treatments. In this way we are progressively reducing the threat posed by a diagnosis of breast cancer and doing this in a personalized fashion."

A possible mechanism for endocrine resistance

An experimental model of breast cancer has yielded exciting new insights into why some breast cancers become resistant to endocrine therapies such as tamoxifen, say researchers from the US and Italy. Their findings could lead to new treatments and prognostic tests for the disease.

"Endocrine resistance in breast cancer is a major clinical issue. Despite years of studies, we still have an incomplete view of the molecular mechanisms that determine endocrine resistance and this limits the potential for developing new therapeutics," explained Dr Luca Malorni, from the Hospital of Prato, Italy and the Breast Center at Baylor College of Medicine, Houston-TX.

Previous observations from his group and others suggested that the transcription factor AP-1 might play a relevant role in endocrine resistance. AP-1 is known to regulate gene expression in response to a variety of stimuli.

To clarify this issue, they used a genetic mechanism to block the AP-1 pathway in mice and cell culture. The researchers report that inhibiting AP-1 enhanced the effects of tamoxifen and delayed the development of tamoxifen resistance. Their data suggest that specific drugs with 'AP-1 inhibitory' effects might be useful in combination with available endocrine agents to develop new, more efficacious treatments.

"Fully understanding the biology behind endocrine resistance is the first step to design new drugs. I think that our data represent such a step forward," Dr Malorni said. "At the same time, our data might be helpful in deriving new biomarkers that could identify patients at higher risk of developing endocrine resistance. This might be an important contribution as today we are able to only partially predict response to endocrine treatment with the available biomarkers."

The researchers propose that endocrine resistance develops when the estrogen receptor 'switches' from its classical direct binding to specific estrogen responsive elements in the tumor genome, to an indirect DNA binding program via AP-1.

"In this light, AP-1 cooperation with estrogen receptor might be considered as a fundamental feature of the endocrine-resistant breast cancer cell. We cannot exclude, however, that AP-1 activity independently of ER is also important. More studies are needed to dissect these different mechanisms," Dr Malorni said.

"I hope that our data could stimulate researchers in this field to consider in their studies the 'switch' in estrogen receptor activity that we are proposing," the researcher added. "For instance, common techniques to evaluate estrogen receptor activity in vitro rely only on measurements of ERE-related functions. Our data suggest that this might be an incomplete view that needs to be implemented with measurements of other estrogen receptor functions as well, such as those that are related to AP-1."

A marker for response to neoadjuvant anthracycline/taxane chemotherapy

Breast cancers that express low levels of the protein mucin-1 tend to respond better to pre-surgical chemotherapy with anthracyclines and taxanes, say German researchers.

"Mucins are present on the internal surface of different organs throughout the body, including the gastrointestinal tract, the lungs and the breast glands," Dr Sinn explained. "In healthy tissues, their role is mainly to protect and to lubricate these surfaces. Mucins, among them mucin-1, have also been shown to be very frequently and abundantly present in tumor cells like breast cancer cells. In cancer, mucin-1 is often present in an altered form and in abnormal locations of the cell. In laboratory experiments, it has been shown that mucin-1 interacts with several cellular signaling networks that may contribute to the malignant behavior of the cells." Interestingly, it is also known that mucin-1 plays a role in the interaction of tumor cells with the immune system of the patient. Abnormal mucin-1 on cancer cells may serve as an antigen that helps to induce the patient's immune system to attack and remove these cells.

The researchers studied tumor biopsy samples from a previous clinical trial of the German Breast Group. In 691 samples, they tested for the presence of the MUC1 protein, and in 268 they explored expression of messenger RNA for the gene. They could detect MUC1 in 656 (95%) cases, and the level of mRNA for the gene varied 1000-fold between tumors.

"High MUC1 protein and mRNA expression were seen more frequently in hormone-receptor positive tumors," Dr Sinn said. "On the other hand, tumors that were hormone receptor negative and HER2 negative had lower MUC1 protein and mRNA expression compared to other subtypes."

The different molecular subtypes of breast cancer, mainly defined by the presence or absence of estrogen receptor and the cell-surface protein HER2, have important implications for the treatment and prognosis of breast cancer. One goal of the current study was to evaluate the frequency of mucin-1 expression among the different subtypes, to provide hints as to which subtypes are most likely to benefit from a therapy that targets mucin-1.

"We could demonstrate that high mucin-1 is more frequently observed in hormone-receptor positive and HER2 negative breast cancer," Dr Sinn said. "The lowest levels were detected in triple negative cases, i.e. tumors without evidence of estrogen-receptor and HER2. However, even in triple negative breast cancers, mucin-1 was high in 44% of cases."

This data indicates an important role for mucin-1 in breast cancer biology that differs among the various breast cancer subtypes, Dr Sinn said. "The results are of particular interest because currently there are tumor vaccines being tested in clinical trials that induce the patient's immune system to attack cells that carry mucin-1. These agents have already shown efficacy in lung cancer and could be also promising agents in the treatment of breast cancer."

When the researchers correlated the expression of the protein and mRNA with the patient's response to chemotherapy, they found that low levels of expression were predictive for pathological complete response —-or eradication of the invasive tumor. This correlation held true for the overall population and in the subgroups of hormone receptor positive, HER2-negative and HR+/HER2- tumors.

"MUC1 is frequently expressed in a large cohort of breast cancers, especially in hormone-receptor positive tumors," the researchers observed. "Its evaluation is feasible by immunohistochemistry and quantitative reverse transcriptase PCR and provides information on therapy response and survival following neoadjuvant chemotherapy."

"Mucin-1 could be a promising target in future cancer therapy," Dr Sinn added. "Agents that stimulate the patient's immune system to attack cells carrying mucin-1 are currently being tested in clinical trials. Determination of mucin-1 by the methods we described in our study may help to select patients that are likely to benefit from such a therapy."

Gene index predicts response to endocrine therapy

Researchers from Germany and the US have confirmed that a 165-gene index can predict survival among breast cancer patients who are treated with endocrine therapies in combination with surgery.

The Sensitivity to Endocrine Therapy (SET) index has been reported in the past to predict survival benefit from adjuvant endocrine therapy, independently of prognosis. In the new study, Dr Thomas Karn from Goethe University in Frankfurt and colleagues set up a blinded study to prospectively validate the index's ability to predict survival in an unpublished retrospective cohort of 307 estrogen-receptor positive primary breast cancers treated solely with endocrine therapy.

Dr Karn and colleagues provided gene expression profiles from 261 patients to the developers of SET without any clinical information. The latters then categorized them into classes based on published pre-specified cutoffs.

Once the analysis had been completed, Dr Karn's group analyzed the relationships between the SET classifications and clinical outcomes for the patients.

They found that patients in the low, intermediate and high SET classes did not differ in age, tumor size, lymph node or HER2 status. However, lower SET significantly correlated with higher grade tumors and negative progesterone-receptor status.

"In the lymph node negative cohort we observed a significant difference in five-year disease-free survival and distant metastasis-free survival for patients with low SET," Dr Karn said. "Furthermore we found no prognostic value of SET in lymph node positive patients."

An exploratory analysis suggested that SET is unrelated to other prognostic signatures, the researchers note.